Neutralization activity in a geographically diverse East London cohort of human immunodeficiency virus type 1-infected patients: clade C infection results in a stronger and broader humoral immune response than clade B infection

There is an urgent need to develop new pathogenic R5 simian/human immunodeficiency viruses (SHIVs) for the evaluation of candidate anti-HIV vaccines in nonhuman primates. Here, we characterize swarm SHIV AD8 stocks, prepared from three infected rhesus macaques with documented immunodeficiency at the time of euthanasia, for their capacity to establish durable infections in macaques following inoculation by the intravenous (i.v.) or intrarectal (i.r.) route. All three viral stocks (SHIV AD8-CE8J , SHIV AD8-CK15 , and SHIV AD8-CL98 ) exhibited robust replication in vivo and caused marked depletion of CD4 ؉ T cells affecting both memory and naïve CD4 ؉ T lymphocyte subsets following administration by either route. Eleven of 22 macaques inoculated with the new SHIV AD8 stocks were euthanized with clinical symptoms of immunodeficiency and evidence of opportunistic infections (Pneumocystis, Candida, and Mycobacterium). A single but unique founder virus, also present in the SHIV AD8-CE8J swarm stock, was transmitted to two animals following a single i.r. inoculation of approximately 3 50% animal infectious doses, which is close to the threshold required to establish infection in all exposed animals. Because the three new SHIV AD8 viruses are mucosally transmissible, exhibited tier 2 sensitivity to anti-HIV-1 neutralizing antibodies, deplete CD4 ؉ T lymphocytes in vivo, and induce AIDS in macaques, they are eminently suitable as challenge viruses in vaccine experiments.

Section: Discussionmentioning

confidence: 98%

“…The neutralization phenotypes (tiers) of SHIV AD8 virus stocks were determined by TZM-bl assay (27) using plasma samples from a cohort study, which exhibited a wide range of neutralizing activities against subtype B HIV-1 isolates, as previously described (7).…”

Section: Methodsmentioning

confidence: 99%

Pathogenicity and Mucosal Transmissibility of the R5-Tropic Simian/Human Immunodeficiency Virus SHIV _AD8 in Rhesus Macaques: Implications for Use in Vaccine Studies

Gautam

Nishimura

Lee

et al. 2012

“…At the virus level, a few studies have analyzed neutralizing activity toward autologous variants, whereas most studies have analyzed neutralizing activity toward heterologous strains. In considering heterologous neutralization, discrepancies might be attributed to the composition of the panels, since HIV isolates exhibit a high degree of variability in sensitivity to neutralization (11,34,35). At the population level, breastfeeding mothers were excluded in some studies but not in others, and timing of transmission was not documented systematically.…”

Section: Discussionmentioning

confidence: 99%

The Breadth and Titer of Maternal HIV-1-Specific Heterologous Neutralizing Antibodies Are Not Associated with a Lower Rate of Mother-to-Child Transmission of HIV-1

Chaillon

Wack

Braibant

et al. 2012

It has been hypothesized that neutralizing antibodies (NAbs) should have broad specificity to be effective in protection against diverse HIV-1 variants. The mother-to-child transmission model of HIV-1 provides the opportunity to examine whether the breadth of maternal NAbs is associated with protection of infants from infection. Samples were obtained at delivery from 57 transmitting mothers (T) matched with 57 nontransmitting mothers (NT) enrolled in the multicenter French perinatal cohort (ANRS EPF CO1) between 1990 and 1996. Sixty-eight (59.6%) and 46 (40.4%) women were infected by B and non-B viruses, respectively. Neutralization assays were carried out with TZM-bl cells, using a panel of 10 primary isolates of 6 clades (A, B, C, F, CRF01_AE, and CRF02_AG), selected for their moderate or low sensitivity to neutralization. Neutralization breadths were not statistically different between T and NT mothers. However, a few statistically significant differences were observed, with higher frequencies or titers of NAbs toward several individual strains for NT mothers when the clade B-infected or non-clade B-infected mothers were analyzed separately. Our study confirms that the breadth of maternal NAbs is not associated with protection of infants from infection.

“…The virus panel included two T-cell-line-adapted (TCLA) strains highly sensitive to neutralization (tier 1A; NL4.3 and MN) and nine primary isolates selected for their high (tier 1B), moderate (tier 2), or low (tier 3) sensitivity to neutralization. Four primary isolates (BX08, BIG, FRO, and KON) of two different clades (B and CRF02_AG) were reported in previous studies (28)(29)(30). We added five primary isolates, including four viruses (94UG103, 92BR020, 93IN905, and 92TH021, of clades A, B, C, and CRF01_AE, respectively) identified as indicators for cross-clade neutralization (31) and one moderately resistant virus (92RW020, clade A) (31).…”

Section: Methodsmentioning

confidence: 99%

Straightforward Selection of Broadly Neutralizing Single-Domain Antibodies Targeting the Conserved CD4 and Coreceptor Binding Sites of HIV-1 gp120

Matz

Kessler

Bouchet

et al. 2013

h Few broadly neutralizing antibodies targeting determinants of the HIV-1 surface envelope glycoprotein (gp120) involved in sequential binding to host CD4 and chemokine receptors have been characterized. While these epitopes show low diversity among various isolates, HIV-1 employs many strategies to evade humoral immune response toward these sensitive sites, including a carbohydrate shield, low accessibility to these buried cavities, and conformational masking. Using trimeric gp140, free or bound to a CD4 mimic, as immunogens in llamas, we selected a panel of broadly neutralizing single-domain antibodies (sdAbs) that bind to either the CD4 or the coreceptor binding site (CD4BS and CoRBS, respectively). When analyzed as monomers or as homo-or heteromultimers, the best sdAb candidates could not only neutralize viruses carrying subtype B envelopes, corresponding to the Env molecule used for immunization and selection, but were also efficient in neutralizing a broad panel of envelopes from subtypes A, C, G, CRF01_AE, and CRF02_AG, including tier 3 viruses. Interestingly, sdAb multimers exhibited a broader neutralizing activity spectrum than the parental sdAb monomers. The extreme stability and high recombinant production yield combined with their broad neutralization capacity make these sdAbs new potential microbicide candidates for HIV-1 transmission prevention.